Apoptosis is a genetically programmed cell death and its deregulation is associated among other pathologies, with cancer. While apoptosis is known to rely on the Bcl-2 family members and caspases, recent data suggested that two major families of serine/threonine phosphatases, PP1 and PP2A, are key actors involved in cell life or cell death decision. The Ser/Thre phosphatase PP2A has been implicated in both, induction and prevention of apoptosis, pointing to a complex interplay of phosphatase actions. Several phosphatases have recently become attractive targets for the treatment of a variety of diseases, including cancers. However, the only clinical drugs targeting a phosphatase are the immunosuppressive cyclosporine A and FK506.
International patent application WO2010/112471 discloses that PP2A interacts with caspase-9, and that a particular sequence from the C-terminal portion of caspase-9 protein is a PP2Ac binding domain. This sequence was identified as being YIETLDDILEQWARSEDL (SEQ ID NO: 1) for murine caspase-9, and as being YVETLDDIFEQWAHSEDL (SEQ ID NO: 2) for human caspase-9. This binding domain to PP2Ac corresponds to amino acid positions 401-418 of murine caspase-9 (NCBI accession number NP_056548), amino acid positions 363-380 of human caspase-9 (NCBI accession number NP_001220).
It was further demonstrated that this caspase-9 PPA2c-binding domain, when fused to a penetrating peptide (fusion peptide DPT-C9 and DPT-C9h), becomes a therapeutic molecule able to deregulate survival of human cells.